Quinolone derivatives are known as synthetic antimicrobial agents having a fused pyridonecarboxylic acid skeleton. It is known that those having a cyclopropyl group at the 1-position exhibit potent antimicrobial activity. Further, quinolone derivatives having a fluorine atom introduced into the 2-position of the cyclopropyl group in a cis-configuration with respect to the fused pyridonecarboxylic acid moiety also exhibit potent antimicrobial activity. These quinolone derivatives are considered to have not only high antimicrobial activity but high safety (see EP-A-0191185 and EP-A-0341493).
Besides antimicrobial activity, in vivo behavior of quinolone derivatives is of importance for safety and efficacy. In vivo behavior of quinolone derivatives, such as oral absorbability, distribution, and excretion, is greatly related to lipophilicity and water-solubility of quinolone molecules. The antimicrobial activity of quinolone derivatives is largely influenced by the structure of a cyclic amine substituent on the 7-position (or a position corresponding to the 7-position) of the quinoline skeleton. However, quinolone compounds with a cyclic amine substituent which have been experimentally verified to exhibit potent antimicrobial activity often fail to clinically show their superiority. The present inventors considered that one of the reasons of such a phenomenon consists in lipophilicity of quinolone molecules and found that quinolone derivatives having a halogenocyclopropyl group, especially a fluorocyclopropyl group, at the 1-position (or a position corresponding to the 1-position) thereof have well-balanced lipophilicity and thereby exhibit high safety and high efficacy as well as excellent antimicrobial activity.
On the other hand, quinolone derivatives having a cis-halogenocyclopropyl group at the 1-position possess excellent properties in terms of antimicrobial activity and safety. These quinolone derivatives contain a pair of enantiomers due to the halogenocyclopropane ring moiety regardless of stereoisomerism at the other position, which is ascribed to the stereochemical relationship between the pyridonecarboxylic acid moiety and the halogen atom on the cyclopropane ring. It is possible to apply a racemic compound of the quinolone derivative, a mixture of enantiomers, as a medicament as such.
Where stereoisomerism exists at a position other than the halogenocyclopropane moiety, particularly at the 7-positioned substituent, such quinolone derivatives contain diastereomers, that is, at least 4 kinds of stereoisomers. A mixture of diastereomers is a mixture of isomers having different physical properties and is difficult to apply as a medicament as such.